Why carry out this study?
|
Many studies reported remarkable cardiovascular efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM), but the differences in cardiovascular efficacy among various subpopulations of patients with T2DM remained unknown. |
What were the subpopulation differences in cardiovascular efficacy of long-acting GLP-1RAs among patients with T2DM? |
What was learned from the study?
|
Our studies suggested that the subpopulation differences in cardiovascular efficacy of long-acting GLP-1RAs were insignificant among subpopulations stratified by different influential factors, and only favorable trends were noticed in the subpopulation with established CVD. |
Our findings might have implications for the management of long-acting GLP-1RAs treatments across various subpopulations of patients with T2DM, as well as the safety of long-acting GLP-1RAs. |
Introduction
Methods
Compliance with Ethics Guidelines
Study Eligibility
Study Identification and Selection
Data Extraction and Quality Assessment
Statistical Analysis
Results
Study Characteristics and Quality Assessment
LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14,752) | Harmony Outcomes (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | |
---|---|---|---|---|---|---|
ID code | NCT01179048 | NCT01720446 | NCT01144338 | NCT02465515 | NCT01394952 | NCT02692716 |
Key inclusion criteria | HbA1c ≥ 7.0%; age ≥ 50 years with CVD, CHF (NYHA class II or III), CKD (stage 3 or higher), or age ≥ 60 years with at least one CV risk factor | HbA1c ≥ 7.0%; age ≥ 50 years with CVD, CHF (NYHA class II or III), CKD (stage 3 or higher), or age ≥ 60 years with at least one CV risk factor | HbA1c 6.5–10.0%; established CVD and primary prevention; age ≥ 18 years | HbA1c ≥ 7.0%; age ≥ 40 years with ASCVD | HbA1c ≤ 9.5%; age ≥ 50 years with established CVD or age ≥ 60 years with at least two CV risk factors; BMI ≥ 23 kg/m2 | Aged ≥ 50 years with established CVD, moderate CKD (stage 3), or aged ≥ 60 years with at least one CV risk factor |
Intervention | Liraglutide vs. placebo | Semaglutide vs. placebo | Exenatide vs. placebo | Albiglutide vs. placebo | Dulaglutide vs. placebo | Semaglutide vs. placebo |
Usage | SI 1.8 mg, once daily | SI 0.5 or 1.0 mg, once weekly | SI 2 mg, once weekly | SI 30 mg, once weekly | SI 1.5 mg, once weekly | Oral 14 mg, once daily |
Dose strategy | Forced increase | Forced increase | Single dose | Clinical titration | Single dose | Increased if tolerated |
Follow-up (median) | 3.8 years | 2.1 years | 3.2 years | 1.6 years | 5.4 years | 15.9 months |
Phase | III | III | III/IV | IV | III | III |
Female sex | 3339 (35.7%) | 1294 (39.2%) | 5605 (38.0%) | 2886 (30.5%) | 4589 (46.4%) | 1005 (31.9%) |
White | 7430 (79.5%) | 2736 (83.0%) | 11,175 (75.8%) | 8024 (84.8%) | 7498 (75.7%) | 2300 (72.3%) |
Asian | 1256 (13.4%) | 272 (8.2%) | 1453 (9.8%) | 464 (4.9%) | 4.4% | 19.8% |
Mean baseline HbA1c (%) | 8.7 ± 1.6 | 8.7 ± 1.5 | 8.1 ± 1.0 | 8.7 ± 1.5 | 7.3 ± 1.1 | 8.2 ± 1.6 |
DM duration (years) | 12.7 ± 8.0 | 13.9 ± 8.1 | 12.0 (7.0, 17.0) | 14.1 ± 8.7 | 10.0 ± 7.2 years | 14.9 ± 8.5 years |
Baseline BMI (kg/m2) | 32.5 ± 6.3 | 32.8 ± 6.0 | 31.8 (28.2, 36.2) | 32.3 ± 5.9 | 32.3 ± 5.7 | 32.3 ± 6.6 |
≥ 30 kg/m2 | 5753 (61.6%) | 2115 (64.1%) | 9338 (63.3%) | 5834 (61.6%) | 6068 (61.3%) | 1902 (59.8%) |
< 30 kg/m2 | 3587 (38.4%) | 1182 (35.9%) | 5414 (36.7%) | 3629 (38.4%) | 3833 (38.7%) | 1279 (40.2%) |
Baseline SBP (mmHg) | 135.9 ± 17.7 | 135.6 ± 17.0 | 135 (124, 145) | 134.7 ± 16.6 | 137.2 ± 16.8 | 135.6 ± 17.6 |
LDL (mmol/L) | 2.3 ± 0.9 | 2.13 ± 1.19 | 2.4 ± 1.0 | 2.1 | 2.56 ± 0.98 | 2.2 ± 0.9 |
Prior established CVD | 81% | 83% | 73% | 100% | 31.4% | 84.6% |
Prior heart failurea | 14.0% | 23.6% | 16.2% | 20% | 8.6% | 12.2% |
Pre-existing retinopathy | 17% | 29.4% | NA | 18.5% | 9.0% | 27.2% |
Primary outcome | Three point-MACE | Three point-MACE | Three point-MACE | Three point-MACE | Three point-MACE | Three point-MACE |
Number of events in long-acting GLP-1RAs group | 608 | 108 | 839 | 334 | 594 | 61 |
HR (95% CI) | 0.87 (0.78, 0.97); P < 0.001 for non-inferiority; P = 0.01 for superiority | 0.74 (0.58, 0.95); P < 0.001 for non-inferiority; P = 0.02 for superiority | 0.91 (0.83, 1.00); P < 0.001 for non-inferiority; P = 0.06 for superiority | 0.78 (0.68, 0.90); P < 0.0001for non-inferiority; P = 0.0006 for superiority | 0.88 (0.79, 0.99); P = 0.026 | 0.79 (0.57, 1.11); P < 0.001 for non-inferiority |
Completion | December 2015 | March 2016 | May 2017 | March 2018 | August 2018 | September 2018 |
Overall Efficacy of Long-Acting GLP-1RAs
LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14,752) | |||||||
---|---|---|---|---|---|---|---|---|---|
Liraglutide | Placebo | HR (95% CI) | Semaglutide | Placebo | HR (95% CI) | Exenatide | Placebo | HR (95% CI) | |
3-point MACE | 608 (13.0) | 694 (14.9) | 0.87 (0.78, 0.97) | 108 (6.6) | 146 (8.9) | 0.74 (0.58, 0.95) | 839 (11.4) | 905 (12.2) | 0.91 (0.83, 1.00) |
CV mortality | 219 (4.7) | 278 (6.0) | 0.78 (0.66, 0.93) | 44 (2.7) | 46 (2.8) | 0.98 (0.65, 1.48) | 340 (4.6) | 383 (5.2) | 0.88 (0.76, 1.02) |
Non-fatal MI | 281 (6.0) | 317 (6.8) | 0.86 (0.73, 1.00) | 47 (2.9) | 64 (3.9) | 0.74 (0.51, 1.08) | 455 (6.2) | 470 (6.4) | 0.95 (0.84, 1.09) |
Non-fatal stroke | 159 (3.4) | 177 (3.8) | 0.86 (0.71, 1.06) | 27 (1.6) | 44 (2.7) | 0.61 (0.38, 0.99) | 155 (2.1) | 177 (2.4) | 0.86 (0.70, 1.07) |
All-cause mortality | 381 (8.2) | 447 (9.6) | 0.85 (0.74, 0.97) | 62 (3.8) | 60 (3.6) | 1.05 (0.74, 1.50) | 507 (6.9) | 584 (7.9) | 0.86 (0.77, 0.97) |
HHF | 218 (4.7) | 247 (5.3) | 0.87 (0.73, 1.05) | 59 (3.6) | 54 (3.3) | 1.11 (0.77, 1.61) | 219 (3.0) | 231 (3.1) | 0.94 (0.78, 1.13) |
Harmony Outcomes (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | HR (95% CI) | P values for trend | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Albiglutide | Placebo | HR (95% CI) | Dulaglutide | Placebo | HR (95% CI) | Semaglutide (oral) | Placebo | HR (95% CI) | |||
3-point MACE | 338 (7) | 428 (9) | 0.78 (0.68, 0.90) | 594 (12.0) | 663 (13.4) | 0.88 (0.79, 0.99)* | 61 (3.8) | 76 (4.8) | 0.79 (0.57, 1.11) | 0.86 (0.82, 0.91) | < 0.001*** |
CV mortality | 122 (2.8) | 130 (3.0) | 0.93 (0.73, 1.19) | 317 (6.4) | 346 (7.0) | 0.91 (0.78, 1.06) | 15 (0.9) | 30 (1.9) | 0.49 (0.27, 0.92) | 0.86 (0.79, 0.95) | 0.002** |
Non-fatal MI | 181 (3.8) | 240 (5.0) | 0.75 (0.61, 0.90) | 205 (4.1) | 212 (4.3) | 0.96 (0.79, 1.16) | 37 (2.3) | 31 (1.9) | 1.18 (0.73, 1.90) | 0.88 (0.80, 0.98) | 0.015** |
Non-fatal stroke | 94 (2.0) | 108 (2.3) | 0.86 (0.66, 1.14) | 135 (2.7) | 175 (3.5) | 0.76 (0.61, 0.95) | 12 (0.8) | 16 (1.0) | 0.74 (0.35, 1.57) | 0.82 (0.74, 0.91) | < 0.001*** |
All-cause mortality | 196 (4.1) | 205 (4.3) | 0.95 (0.79, 1.16) | 536 (10.8) | 592 (12.0) | 0.90 (0.80, 1.01) | 23 (1.4) | 45 (2.8) | 0.51 (0.31, 0.84) | 0.88 (0.81, 0.95) | 0.001*** |
HHF | 188 (4.0) | 218 (5.0) | 0.85 (0.70, 1.04) | 213 (4.3) | 226 (4.6) | 0.93 (0.77, 1.12) | 21 (1.3) | 24 (1.5) | 0.86 (0.48, 1.55) | 0.91 (0.83, 0.99) | 0.036** |
Analyses of Subpopulation Differences
LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14,752) | ||||
---|---|---|---|---|---|---|
HR (95% CI) | P1 | HR (95% CI) | P1 | HR (95% CI) | P1 | |
Baseline age | ||||||
< 60/65/66 years | 0.78 (0.62, 0.97) | 0.27 | 0.74 (0.52, 1.05) | 0.95 | 1.05 (0.92, 1.21) | 0.005 |
≥ 60/65/66 years | 0.90 (0.79, 1.02) | 0.72 (0.61, 1.02) | 0.80 (0.71, 0.91) | |||
Sex | ||||||
Male | 0.86 (0.75, 0.98) | 0.84 | 0.68 (0.50, 0.92) | 0.45 | 0.94 (0.84, 1.05) | 0.44 |
Female | 0.88 (0.72, 1.08) | 0.84 (0.54, 1.31) | 0.86 (0.73, 1.03) | |||
Baseline BMI | ||||||
< 30 kg/m2 | 0.96 (0.81, 1.15 | 0.15 | 0.58 (0.39, 0.87) | 0.16 | 0.94 (0.79, 1.10) | 0.59 |
≥ 30 kg/m2 | 0.82 (0.71, 0.94) | 0.84 (0.61, 1.16) | 0.89 (0.79, 1.00) | |||
Region | ||||||
Europe | 0.82 (0.68, 0.98) | 0.20 | 0.62 (0.34, 1.13) | 0.58 | 1.00 (0.87, 1.15) | 0.39 |
North America | 1.01 (0.84, 1.22) | 0.87 (0.57, 1.34) | 0.84 (0.72, 0.97) | |||
Asia | 0.62 (0.37, 1.04) | NA | 0.85 (0.62, 1.18) | |||
Rest of the world | 0.83 (0.68, 1.03) | 0.68 (0.48, 0.98) | 0.92 (0.67, 1.26) | |||
Race | ||||||
White | 0.90 (0.80, 1.02) | 0.32 | 0.76 (0.58, 1.00) | 0.88 | 0.95 (0.85, 1.05) | 0.61 |
Black | 0.87 (0.59, 1.27) | 0.72 (0.23, 2.28) | 0.67 (0.45, 0.99) | |||
Asian | 0.70 (0.46, 1.04) | 0.58 (0.25, 1.34) | 0.81 (0.57, 1.14) | |||
Others | 0.61 (0.37, 1.00) | 0.46 (0.008, 2.50) | 0.92 (0.63, 1.34) | |||
Hb1Ac | ||||||
< 7.2%/8%/8.3%/8.5% | 0.89 (0.76, 1.05) | 0.58 | 0.72 (0.50, 1.03) | 0.94 | 0.91 (0.80, 1.05) | 0.97 |
≥ 7.2%/8%/8.3%/8.5% | 0.84 (0.72, 0.98) | 0.74 (0.52, 1.04) | 0.91(0.80, 1.04) | |||
Duration of DM | ||||||
≤ 10/11/15 years | 0.82 (0.70, 0.97) | 0.42 | 0.73 (0.48, 1.12) | 0.99 | 0.85 (0.62, 1.18) | 0.18 |
> 10/11/15 years | 0.90 (0.78, 1.04) | 0.73 (0.54, 0.99) | 0.90 (0.79, 1.04) | |||
Estimated GFR | ||||||
≥ 60 ml/min/1.73 m2 | 0.94 (0.83, 1.07) | 0.01 | 0.67 (0.48, 0.92) | 0.37 | 0.86 (0.77, 0.97) | 0.12 |
< 60 ml/min/1.73 m2 | 0.69 (0.57, 0.85) | 0.84 (0.57, 1.25) | 1.01 (0.86, 1.19) | |||
History of HF | ||||||
Yes | 0.94 (0.72, 1.21) | 0.53 | 1.03 (0.64, 1.66) | 0.09 | 0.97 (0.81, 1.16) | 0.50 |
No | 0.85 (0.76, 0.96) | 0.64 (0.48, 0.86) | 0.90 (0.81, 1.00) | |||
CVD status | ||||||
With established CVD | 0.83 (0.74, 0.93) | 0.04 | 0.72 (0.55, 0.93) | 0.49 | 0.90 (0.82, 1.00) | 0.50 |
Without established CVD | 1.20 (0.86, 1.67) | 1.00 (0.41, 2.46) | 0.99 (0.77, 1.28) |
Harmony Outcomes (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | HR (95% CI) | P1 | ||||
---|---|---|---|---|---|---|---|---|
HR (95% CI) | P1 | HR (95% CI) | P1 | HR (95% CI) | P1 | |||
Baseline age | ||||||||
< 60/65/66 years | 0.66 (0.53, 0.82) | 0.037 | 0.92 (0.78, 1.09) | 0.57 | 0.51 (0.29, 0.90) | 0.05 | 0.80 (0.67, 0.97) | 0.821 |
≥ 60/65/66 years | 0.85 (0.61, 1.17) | 0.86 (0.74, 1.00) | 1.04 (0.68, 1.59) | 0.84 (0.79, 0.91) | ||||
Sex | ||||||||
Male | 0.82 (0.6, 0.97) | 0.227 | 0.90 (0.79,1.04) | 0.60 | 0.72 (0.50, 1.05) | 0.28 | 0.87 (0.81, 0.93) | 0.605 |
Female | 0.67 (0.50, 0.89) | 0.85 (0.71, 1.02) | 1.16 (0.54, 2.51) | 0.85 (0.78, 0.92) | ||||
Baseline BMI | ||||||||
< 30 kg/m2 | 0.72 (0.57, 0.91) | 0.435 | 0.91 (0.76, 1.08) | 0.67 | 0.61 (0.36,1.03) | 0.20 | 0.85 (0.74, 0.97) | 0.295 |
≥ 30 kg/m2 | 0.81 (0.68, 0.97) | 0.86 (0.75, 1.00) | 0.95 (0.61, 1.45) | 0.82 (0.76, 0.89) | ||||
Region | ||||||||
Europe | 0.73 (0.60, 0.88) | 0.691 | 0.77 (0.65, 0.90) | 0.0080 | NA | 0.82 (0.71, 0.94) | 0.967 | |
North America | 0.92 (0.70, 1.19) | 1.14 (0.89, 1.47) | NA | 0.94 (0.84, 1.06) | ||||
Asia | 0.69 (0.28, 1.69) | 0.54 (0.32, 0.89) | NA | 0.72 (0.57, 0.9) | ||||
Rest of the world | 0.76 (0.50, 1.16) | 0.99 (0.81, 1.21) | NA | 0.87 (0.77, 0.98) | ||||
Race | ||||||||
White | 0.76 (0.64, 0.89) | 0.065 | 0.90 (0.79, 1.02) | 0.77 | 0.83 (0.56, 1.23) | 0.14 | 0.88 (0.82, 0.94) | 0.148 |
Black | 2.60 (1.14, 5.94) | 0.77 (0.51, 1.17) | 5.67 (0.66,48.51) | 0.95 (0.65, 1.4) | ||||
Asian | 0.73 (0.36, 1.48) | 0.71 (0.40, 1.24) | 0.44 (0.20, 0.97) | 0.71 (0.58, 0.88) | ||||
Others | 0.71 (0.51, 1.00) | 0.92 (0.67, 1.28) | 1.04 (0.06,16.59) | 0.81 (0.67, 0.97) | ||||
Hb1Ac | ||||||||
< 7.2%/8%/8.3%/8.5% | 0.94 (0.73, 1.22) | 0.90 (0.76, 1.06) | 0.75 | 0.81 (0.53, 1.24) | 0.77 | 0.89 (0.82, 0.97) | 0.227 | |
≥ 7.2%/8%/8.3%/8.5% | 0.71 (0.60, 0.84) | 0.86 (0.74, 1.00) | 0.73 (0.42, 1.26) | 0.83 (0.76, 0.90) | ||||
Duration of DM | ||||||||
≤ 10/11/15 years | 0.67 (0.51, 0.87) | 0.87 (0.75, 1.01) | 0.88 | NA | 0.82 (0.74, 0.90) | 0.301 | ||
> 10/11/15 years | 0.82 (0.70, 0.98) | 0.90 (0.77, 1.06) | NA | 0.87 (0.81, 0.94) | ||||
Estimated GFR | ||||||||
≥ 60 ml/min/1.73 m2 | 0.72 (0.61, 0.86) | NA | 0.81 (0.54, 1.22) | 0.80 | 0.82 (0.73, 0.93) | 0.671 | ||
< 60 ml/min/1.73 m2 | 0.93 (0.73, 1.20) | NA | 0.74 (0.41, 1.33) | 0.85 (0.71, 1.02) | ||||
History of HF | ||||||||
Yes | 0.70 (0.54, 0.90) | 0.278 | NA | NA | 0.89 (0.75, 1.05) | 0.553 | ||
No | 0.82 (0.69, 0.98) | NA | NA | 0.84 (0.76, 0.92) | ||||
CVD status | ||||||||
With established CVD | 0.78 (0.68, 0.90) | – | 0.87 (0.74, 1.02) | 0.97 | 0.83 (0.58, 1.17) | 0.44 | 0.84 (0.80, 0.89) | 0.171 |
Without established CVD | –a | 0.87 (0.74, 1.02) | 0.51 (0.15, 1.68) | 0.94 (0.82, 1.07) |
Safety Outcomes
LEADER | SUSTAIN 6 | EXSCEL | ||||
---|---|---|---|---|---|---|
Liraglutide (n = 4668) | (n = 4672) | Semaglutide (n = 1648) | (n = 1649) | Exenatide (n = 7356) | (n = 7396) | |
Severe hypoglycemia | 114 (2.4%) | 153 (3.3%) | 369 (22.4%) | 350 (21.2%) | 247 (3.4%) | 219 (3.0%) |
Pancreatitis | 18 (0.4%) | 25 (0.5%) | 9 (0.55%) | 12 (0.72%) | 26 (0.4%) | 22 (0.3%) |
Any cancera | 296 (6.3%) | 279 (6.0%) | 66 (4.0%) | 70 (4.2%) | 355 (4.8%) | 361 (4.9%) |
Thyroid neoplasms | 5 (< 0.1%) | 3 (< 0.1%) | 1 (< 0.1%) | 2 (0.1%) | NA | NA |
Pancreatic cancer | 13 (0.3%) | 5 (0.1%) | 1 (0.06%) | 4 (0.24%) | 15 (0.2%) | 16 (0.2%) |
Retinopathy | 106 (2.3%) | 92 (2.0%) | 50 (3.0%) | 29 (1.8%) | 214 (2.9%) | 238 (3.2%) |
Serious gastrointestinal eventsb | 407 (8.7%) | 361 (7.7%) | 75 (4.5%) | 50 (3.0%) | 220 (3.0%) | 216 (2.9%) |
AEs leading to discontinuation | 444c (9.5%) | 339c (7.3%) | 214d (13.0%) | 110d (6.7%) | 108c (1.5%) | 104c (1.4%) |
SAE | 2320 (49.7%) | 2354 (50.4%) | 565 (34.3%) | 627 (38.0%) | 1234 (16.8%) | 1222 (16.6%) |
Harmony | REWIND | PIONEER-6 | OR (95% CI) | P values for trend | ||||
---|---|---|---|---|---|---|---|---|
Albiglutide (n = 4371) | (n = 4372) | Dulaglutide (n = 4949) | (n = 4952) | Oral Semaglutide (n = 1591) | (n = 1592) | |||
Severe hypoglycemia | 31 (0.71%) | 55 (1.3%) | 64 (1.3%) | 74 (1.5%) | 23 (1.4) | 13 (0.8) | 0.95 (0.77, 1.16) | 0.597 |
Pancreatitis | 10 (0.21%) | 7 (0.15%) | 23 (0.5%) | 13 (0.3%) | 1 (0.1) | 3 (0.2) | 0.92 (0.63, 1.34) | 0.657 |
Any cancera | 87 (2.0%) | 112 (2.6%) | 351 (7.1%) | 348 (7.0%) | 41 (2.6%) | 48 (3.0%) | 0.97 (0.89, 1.05) | 0.449 |
Thyroid neoplasms | 0 | 0 | 7 (0.144%) | 3 (0.06%) | NA | NA | – | – |
Pancreatic cancer | 6 (0.14%) | 5 (0.11%) | 19 (0.4%) | 12 0.2%) | NA | NA | 1.31 (0.79, 2.17) | 0.300 |
Retinopathy | 78 (1.6%) | 89 (1.9%) | 95 (1.9%) | 76 (1.5%) | 113 (7.1) | 101 (6.3) | 1.09 (0.92, 1.29) | 0.316 |
Serious gastrointestinal eventsb | 92 (1.9%) | 87 (1.7%) | 120 (2.4%) | 117 (2.4%) | 108 (6.8%) | 26 (1.6%) | 1.37 (1.02, 1.83) | 0.037** |
AEs leading to discontinuation | NA | NA | 2092e (42.3%) | 2171e (43.8%) | 184c (11.6%) | 104c (6.5%) | 1.38 (1.01, 1.88) | 0.046** |
SAE | 932 (19.8%) | 1022 (21.7%) | NA | NA | 301 (18.9%) | 358 (22.5%) | 0.92 (0.85, 1.00) | 0.039** |